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This report shows an unusual form of biochemistry that contributes to certain forms of ALS/FTLD. Typically, DNA is transcribed to make an RNA, and the RNA is translated to make a protein. This translation almost always requires a signal that says “Translation begins here.” This signal is an ATG codon in the sequence. Moreover, typically one RNA produces only one protein. Most, but not all, forms of ALS/FTLD are caused by an expanded GGGGCC repeat in the DNA of the C9ORF72 gene which is transcribed to an RNA with the expanded repeat. This paper suggests that this repeat is translated in a manner that does not require that start signal. This repeat-associated non-ATG translation (RAN-translation) of the C9ORF72 hexanucleotide repeat resembles that initially observed by Laura P. Ranum's lab for myotonic dystrophy type 1 and spinocerebellar ataxia type 8 trinucleotide repeats, CTG, and CAG (Zu et al., 2011). For the ALS/FTLD expanded repeat, three different RNA proteins are produced and present in patients' brains. The presence of RAN-translated protein products in brains of ALS/FTLD patients who have the repeat expansion mutation, but not in patients with other variants of ALS/FTLD without the expansion, or in non-affected individuals, is striking for several reasons: First, this finding provides further support for the existence of this totally strange form of translation initially observed by Ranum and colleagues. Second, it reveals the potential involvement of dipeptide repeats in pathogenesis. Third, it further subclassifies the forms of this serious set of motor neuron diseases; ALS/FTLD with and without expansions and RAN-translation products. These are exciting advances for ALS/FTLD research, but only more research will tell what is the role, if any, of these RAN products in disease. Stay tuned!

This paper represents an important step in understanding the molecular processes in FTLD/ALS, and expands the basic concepts of biological processes. Furthermore, the dipeptide repeat (DPR) protein antibodies will provide a powerful research and diagnostic tool for our field.

The big question now is the relevance of DPRs to disease. The DPR expression is reported in patient cerebellum and hippocampus, which do not have a direct connection with FTLD/ALS; therefore, are DPRs expressed to that level in regions directly connected with the disease, such as frontal cortex or spinal cord? As far as it is known, repeat-associated non-ATG-initiated (RAN) translation requires hairpin formation. Following suggestions that GGGGCC may form G-quadruplex structures (in vitro), several explanations for the translation and its anatomical distribution come to mind: 1) RAN translation can be initiated also from G-quadruplex structures; 2) G-guadruplexes do not form in vivo and the hairpin is the major structure of the RNA repeat; 3) different regions of the brain have a different complement of RNA-binding factors, and hippocampus and cerebellum may have an environment inducive for hairpin formation. Those conditions may be absent in frontotemporal cortex and spinal cord; 4) there are temporal and spatial differences in the expression level of the GGGGCC repeat, such that GGGGCC repeat expression is increased in hippocampus and cerebellum with the onset of disease.